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381
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325
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112580
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706944
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706629
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365
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295
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119
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366
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111636
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213
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706964
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139
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179
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326
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108554
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380
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706945
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364
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296
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211
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706602
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114927
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112338
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212
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60
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159
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178
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383
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706672
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327
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114133
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112965
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115086
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297
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112628
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706567
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215
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706962
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706547
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368
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61
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110825
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706631
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382
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706671
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112820
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328
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113614
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706800
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113253
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706652
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706628
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706600
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298
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214
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112399
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367
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62
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108916
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706752
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300
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108237
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115
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706605
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361
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706670
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291
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114205
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155
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99
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320
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107304
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301
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341
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706698
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217
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706968
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112314
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116
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360
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292
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706941
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236
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706969
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154
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322
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321
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302
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216
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706606
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706750
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340
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19
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344
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293
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117
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239
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323
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303
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112242
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158
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219
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343
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118
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294
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110716
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238
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324
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156
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157
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304
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342
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218
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346
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231
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111
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706590
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131
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112448
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250
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notes: This model is from the article: An Integrated Mathematical Model of Thrombin-, Histamine-and VEGF-Mediated Signalling in Endothelial Permeability. Wei X, Han B, Zhang J, Liu X, Tan C, Jiang Y, Low B, Tidor B, Chen Y. BMC Syst Biol. 2011 Jul 15;5:112. 21756365 , Abstract: Endothelial permeability is involved in injury, inflammation, diabetes and cancer. It is partly regulated by the thrombin-, histamine-, and VEGF-mediated myosin-light-chain (MLC) activation pathways. While these pathways have been investigated, questions such as temporal effects and the dynamics of multi-mediator regulation remain to be fully studied. Mathematical modeling of these pathways facilitates such studies. Based on the published ordinary differential equation models of the pathway components, we developed an integrated model of thrombin-, histamine-, and VEGF-mediated MLC activation pathways. RESULTS: Our model was validated against experimental data for calcium release and thrombin-, histamine-, and VEGF-mediated MLC activation. The simulated effects of PAR-1, Rho GTPase, ROCK, VEGF and VEGFR2 over-expression on MLC activation, and the collective modulation by thrombin and histamine are consistent with experimental findings. Our model was used to predict enhanced MLC activation by CPI-17 over-expression and by synergistic action of thrombin and VEGF at low mediator levels. These may have impact in endothelial permeability and metastasis in cancer patients with blood coagulation. CONCLUSION: Our model was validated against a number of experimental findings and the observed synergistic effects of low concentrations of thrombin and histamine in mediating the activation of MLC. It can be used to predict the effects of altered pathway components, collective actions of multiple mediators and the potential impact to various diseases. Similar to the published models of other pathways, our model can potentially be used to identify important disease genes through sensitivity analysis of signalling …
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306
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376
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40
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308
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379
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370
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307
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185
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289
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44
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288
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372
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187
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287
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160
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706737
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105
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112109
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112977
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115501
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315
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203
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356
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706974
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73
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354
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706955
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316
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202
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109955
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110728
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355
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706616
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229
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200
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706686
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353
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393
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313
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108151
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201
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228
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314
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112048
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392
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706742
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706646
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72
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89
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311
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391
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351
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113831
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227
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207
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331
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113517
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310
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706668
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312
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115221
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350
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226
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390
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50
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206
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330
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127
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225
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205
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168
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128
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204
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262
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144
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282
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261
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146
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335
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122
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280
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286
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109316
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111188
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107728
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175
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109522
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114867
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12
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706723
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113855
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706690
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58
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110304
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706705
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114181
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107015
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706772
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37
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112881
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82
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706648
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17
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172
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386
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114915
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115012
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108965
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108542
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110922
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78
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109193
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114771
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113061
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110364
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57
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109619
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706970
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113037
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110039
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706745
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114686
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706773
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38
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107353
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112869
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706647
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388
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107099
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81
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387
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114266
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173
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108347
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706725
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107934
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111490
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77
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18
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113121
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319
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115949
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56
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706707
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706973
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111914
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35
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106967
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80
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198
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116298
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706746
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706931
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706726
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384
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15
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106907
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318
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170
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76
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706812
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107862
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116057
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706775
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55
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706706
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706972
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75
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115281
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111104
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706727
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199
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114843
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36
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706747
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109025
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116009
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109266
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317
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171
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385
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16
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115525
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111164
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112084
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706811
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299
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